The present invention relates generally to the preservation of pharmaceutical compositions. In particular, the present invention relates to the use of fatty acid/amino acid soaps to prevent or to reduce binding of the antimicrobial components of topically administrable pharmaceutical compositions to other components contained therein, thereby improving the antimicrobial efficacy of such compositions.
In recent years, a number of ophthalmic compositions have been introduced that contain a variety of components, such as carboxyvinyl polymers (e.g., Carbopol(copyright)), ion exchange resins (e.g., Amberlite(copyright)), or other large polyelectrolytes, which provide sustained release of the ophthalmic agent(s), as well as increased patient comfort. Such compositions are described, for example, in U.S. Pat. No. 4,911,920 (Jani et al.). Although these compositions are comfortable and have sustained release characteristics, cationic antimicrobials, such as benzalkonium chloride (BAC), which are often added as preservatives to such compositions, tend to bind to the anionic polyelectrolytes present in the formulations, resulting in loss of antimicrobial effectiveness.
Sarcosinate surfactants are composed of acylated sarcosines. Sarcosine (CH3xe2x80x94NHxe2x80x94CH2xe2x80x94COOH), an amino acid normally found in starfish and sea urchins, is chemically related to glycine (NH2xe2x80x94CH2xe2x80x94COOH), a basic amino acid in mammals. Common fatty acids and their derivatives utilized in the manufacture of sarcosinate surfactants are lauric, oleic, and myristic acids and their esters and halides. Because of their mildness, sarcosinate surfactants have been utilized in shampoos, mouthwashes, skin cleansers, sunscreens, aerosol shaving lathers and other personal care products. To date, the main applications of these types of surfactants have been in the cosmetic industry. For example, European Patent Application No. 0 194 097 (Schmidt et al.), assigned to Procter and Gamble, mentions sodium lauroyl sarcosinate as the mild anionic surfactant utilized in an aerosol skin-cleansing and moisturizer mousse.
U.S. Pat. No. 5,520,920 (Castillo, et al.) discloses the use of certain modified sarcosinates and lactylates to enhance antimicrobial effectiveness of ophthalmic compositions, particularly in the case where cationic preservatives otherwise bind to anionic polyelectrolytes. The modified sarcosinates have the formula: 
wherein: R1=C4-C27 saturated or unsaturated hydrocarbon;
M=H or a pharmaceutically acceptable salt; and
n=1, 2 or 3.
Representative modified sarcosinates include those sold under the Hamposyl(copyright) trade name, such as lauroyl sarcosine (Hamposyl(copyright) L), oleoyl sarcosine (Hamposyl(copyright) O), myristoyl sarcosine (Hamposyl(copyright) M), cocoyl sarcosine (Hamposyl(copyright) C.), stearoyl sarcosine (Hamposyl(copyright) S), and pelargodoyl sarcosine (Hamposyl(copyright) P). Representative lactylates include sodium capryl lactylate (Pationice(copyright) 122A).
Additional solutions to the problem of cationic preservativexe2x80x94anionic polyelectrolyte binding problem in topically administrable pharmaceutical compositions are desirable.
Fatty acid/amino acid soaps are known and include, for example, those surfactants sold under the Aminosoap(copyright) trade name (Ajinomoto Co., Inc., Tokyo, Japan). According to product brochures, Aminosoape surfactants are used in hair and body care (hair shampoo, body wash and bath foam), facial care (facial cleanser, facial washing foam, facial washing creme, and make-up remover), and household and health care.
The present invention provides a method of enhancing the preservative efficacy of topically administrable pharmaceutical compositions containing an anionic polyelectrolyte and a cationic preservative, but lacking a phospholipid. According to the method of the present invention, a fatty acid/amino acid soap is added to the topically administrable pharmaceutical composition.
Although the Applicants do not wish to be bound to a particular theory, it is believed that the addition of fatty acid/amino acid soaps to the compositions results in the release of the bound cationic preservative from the anionic polyelctrolyte by the formation of a loose and reversible surfactant-preservative complex. The surfactant-preservative complex has antimicrobial effectiveness. Alternatively, the soaps may themselves possess antimicrobial activity.
Regardless of the mechanism, the fatty acid/amino acid soaps of the present invention improve the preservative efficacy of topically administrable pharmaceutical compositions. Accordingly, the present invention also relates to topically administrable pharmaceutical compositions containing one or more pharmaceutically active agents, an anionic polyelectrolyte, a cationic preservative, and a fatty acid/amino acid soap.
Unless indicated otherwise, all amounts of composition ingredients expressed in percentage terms are expressed as weight/weight.
Fatty acid/amino acid soaps useful in the preservative systems of the present invention are those wherein the fatty acid component is derived from a C8-C24 fatty acid and the amino acid component is selected from the group consisting of lysine and arginine. Preferably, the fatty acid component is selected from the group consisting of cocoyl, linoleoyl, lauroyl, myristoyl, stearoyl, oleoyl, and pelargodoyl fatty acid residues. Such fatty acid/amino acid soaps are commercially available or can be made by known methods. For example, the soap where the fatty acid component is cocoyl and the amino acid component is derived from arginine is commercially available as AMINOSOAP AR-12 from Ajinomoto Co., Inc. (Tokyo, Japan). The soap where the fatty acid component is cocoyl and the amino acid component is derived from lysine is available as AMINOSOAP LYC-12.
In general, the amount of fatty acid/amino acid soap present in the compositions of the present invention is from about 0.001 to about 1%, preferably from about 0.01 to about 0.2%, and most preferably from about 0.03 to about 0.12%. For topical ophthalmic preparations, the concentration of the fatty acid/amino acid soap should not be so high that it causes severe discomfort.
The compositions of the present invention contain cationic antimicrobials and anionic polyelectrolytes. Cationic antimicrobials are known in the art and include, but are not limited to, quaternary ammonium compounds, such as benzalkonium chloride and polyquaternium-1. Anionic polyelectrolytes include high molecular weight, anionic mucomimetic polymers (e.g., carboxyvinyl polymers such as Carbopol(copyright)), polystyrene sulfonic acid polymers, cationic exchange resins (e.g., Amberlite(copyright) or Dowex(copyright)), and the like.
High molecular weight, anionic mucomimetic polymers have a molecular weight between about 50,000 and 6 million. The polymers are characterized as having carboxylic acid functional groups and preferably contain between 2 and 7 carbon atoms per functional group. Suitable high molecular weight, anionic polymers are carboxyvinyl polymers, preferably those called Carbomers, e.g., Carbopol(copyright) (B.F. Goodrich Co., Cleveland, Ohio). Specifically preferred are Carbopol(copyright) 934P, Carbopole 974P and Carbopol(copyright) 940. Other suitable high molecular weight, anionic polymers include: alginates, carrageenans, natural gums (xanthan, karaya and tragacanth) and carboxy methyl cellulose. Such polymers will typically be employed in an amount between about 0.05 and about 6%, depending on the desired viscosity of the composition. Pourable liquid compositions generally comprise an amount of the polymer between about 0.05 and about 2%.
Cation exchange resins are characterized as either strongly acidic, such as those having sulfonic acid or sulfuric acid functionality, or weakly acidic, such as those having carboxylic acid functionality. Such resins are readily available, for example, from Rohm and Haas (Philadelphia, Pa.) under the name Amberlitee and from Dow Chemical Co. (Midland, Mich.) under the name Dowex(copyright). The average particle size of the commercially available forms of the resins is about 40 to 150 microns. The particle size of the resin is critical for topically administrable ophthalmic compositions. Accordingly, for topically administrable ophthalmic compositions, commercially available resin particles are reduced by known techniques, including ball milling, to a particle size of about 20 xcexcm or less such that the average particle size is  less than 10 xcexcm, and are preferably reduced to a particle size of about 10 xcexcm or less. Ion exchange resins are typically used in an amount from about 0.05 to about 10%.
Anionic mucomimetic polymers and cation exchange resins are discussed in greater detail in U.S. Pat. No. 4,911,920 issued Mar. 27, 1990, the entire contents of which are hereby incorporated by reference herein.
The polystyrene sulfonic acid polymers (and their salts) useful in the compositions of the present invention comprise the following repeating unit: 
wherein: W=H or CH3; and
x=an integer such that the molecular weight of the polystyrene sulfonic acid polymer is from about 10,000 to 1.6 million.
In the preferred polystyrene sulfonic acid polymers of formula I, W=H and the molecular weight is between about 500,000 to about 1,000,000, preferably about 600,000. If present in the compositions of the present invention, the polystyrene sulfonic acid polymers of formula I comprise less than about 8%, preferably less than about 5%.
The active ingredient or ingredients that can be included in the compositions of the present invention include all ophthalmic, dermatological, otic or nasal agents that can be topically applied. For example, such ophthalmic agents include (but are not limited to): anti-glaucoma agents, such as beta-blockers (e.g., betaxolol and timolol), muscarinics (e.g., pilocarpine), prostaglandins, carbonic anhydrase inhibitors (e.g., acetazolamide, methazolamide and ethoxzolamide), dopaminergic agonists and antagonists, and alpha adrenergic receptor agonists, such as para-amino clonidine (also known as apraclonidine) and brimonidine; anti-infectives, such as ciprofloxacin; non-steroidal and steroidal anti-inflammatories, such as suprofen, ketorolac, dexamethasone, rimexolone and tetrahydrocortisol; proteins; growth factors, such as EGF; and anti-allergic agents, such as cromolyn sodium, emedastine and olopatadine. Compositions of the present invention may also include combinations of active ingredients. Most preferred are topically administrable ophthalmic compositions.
The compositions of the present invention can also include other components, for example, pharmaceutically acceptable buffers; tonicity agents; comfort-enhancing agents; solubilizing aids; pH adjusting agents; antioxidants; and stabilizing agents. The compositions may also contain additional preservatives (in conjunction with the cationic preservatives addressed above). As will be appreciated by those skilled in the art, the compositions may be formulated in various dosage forms suitable for topical delivery, including solutions, suspensions, emulsions, and gels.
The compositions of the present invention do not contain a phospholipid.